Cefadroxil Comparable to Cephalexin: Minimum Inhibitory Concentrations among Methicillin-Susceptible Staphylococcus aureus Isolates from Pediatric Musculoskeletal Infections

ABSTRACT Cephalexin and cefadroxil are oral first-generation cephalosporins used to treat methicillin-susceptible Staphylococcus aureus (MSSA) infections. Despite its shorter half-life, cephalexin is more frequently prescribed, although cefadroxil is an appealing alternative, given its slower clearance and possibility for less frequent dosing. We report comparative MIC distributions for cefadroxil and cephalexin, as well as for oxacillin, cephalothin, ceftaroline, and cefazolin, for 48 unique clinical MSSA isolates from pediatric patients with musculoskeletal infections. Both cefadroxil and cephalexin had MIC50 values of 2 μg/mL and MIC90 values of 4 μg/mL. MIC50s for oxacillin, cephalothin, and ceftaroline were ≤0.25 μg/mL, and cefazolin’s MIC50 was 0.5 μg/mL. While cefadroxil and cephalexin MICs are higher than those for other active agents, the distributions of MICs for cefadroxil and cephalexin are statistically equivalent, suggesting similar in vitro MSSA activities. Cefadroxil should be further considered an alternative agent to cephalexin, although additional work is needed to identify the optimal dose and frequency of these antibiotics for the treatment of serious MSSA infections. IMPORTANCE Cephalexin and cefadroxil are oral antibiotics that are used to treat serious infections due to the bacteria MSSA. While cephalexin is used more commonly, cefadroxil is excreted from the body more slowly; this generally allows patients to take cefadroxil less frequently than cephalexin. In this study, we compared the abilities of cefadroxil, cephalexin, and several other representative intravenous antibiotics to inhibit the growth of MSSA in the laboratory. Bacterial samples were obtained from children with bone, joint, and/or muscle infections caused by MSSA. We found that cefadroxil and cephalexin inhibited the growth of MSSA at similar concentrations, suggesting similar antibacterial potencies. The selected intravenous antistaphylococcal antibiotics generally inhibited bacterial growth with lower antibiotic concentrations. Based on these results, cefadroxil should be further considered an alternative oral antibiotic to cephalexin, although future research is needed to identify the optimal dose and frequency of these antibiotics for serious infections.

1. Introduction. The authors comment that some experts recommend thrice daily cephalexin rather than four times daily out of concerns for adherence. Of note, in two recent publications, MSSA osteoarticular infections were treated with three times daily cephalexin with high levels of treatment success (Ramchandar N, et al. 2020. Pediatr Infect Dis J 39:523-525;McNeil et al. Antimicrob Agents Chemother. 2020;64: e00703) and in one of these papers tid dosing was comparable to qid dosing in terms of efficacy (albeit uncontrolled and sample size limiting).
2. Introduction. The authors write, "While cephalexin is typically dosed 3-4 times per day, cefadroxil can likely be dosed 2-3 times per day" and reference the package insert. Some expansion on this is probably warranted. Cefadroxil is approved for treatment of UTI, SSTI and streptococcal pharyngitis in children with daily or bid dosing. Why would three times daily dosing of cefadroxil be needed?
3. Methods. The authors should clarify that only a single isolate was used per clinical case (for example, a blood culture and bone aspirate were not used from the same patient). My assumption from the paper was that each isolate was truly unique although this should be made explicit.
4. Results. The MIC data as presented in the table are interesting and the methods appear rigorous. In the text, may consider reporting the MIC50 and MIC90 as this is the more common practice rather than median and IQR.

Introduction
Line 62 Suggest referencing the sentence "However, three-times daily (TID) dosing is commonly used given concerns regarding adherence with QID dosing" could consider the recent publication https://journals.lww.com/pidj/Fulltext/2020/06000/Twice__and_Thrice_daily_Cephalexin_Dosing_for.12.aspx Line 66 "cefadoxil is an appealing alternative to cephalexin based on its longer half-life, ~1.5-2 hours in adults (4, 5). While cephalexin is typically dosed 3-4 times per day, cefadroxil can likely be dosed 2-3 times per day (6)." Is this the dosing interval of 2-3 times per day recommended in adults or children or both, recommend specifying?
Line 59 "For oral therapy, cephalexin is most commonly used given its favorable side effect profile and low cost." Is there a reference for this at all and are you referring to in children (I think this is commonly the case in paediatrics but thought that in adults oxacillin is more commonly favoured but again jurisdiction dependent)?
For the below comments in the introduction and discussion respectively: Line 68 "Despite these theoretical benefits, cefadroxil has not gained widespread use, especially in pediatrics, in part due to the paucity of pediatric pharmacokinetic and pharmacodynamic (PK/PD) data and uncertainty about cefadroxil's range of minimum inhibitory concentrations line 144 "Given the limited data available, the concentrations needed for adequate time above our described MICs are likely achievable with commonly used oral dosing strategies" Is there any PK/PD data in children (even down to 12) for cefadroxil? If so it would be helpful for the reader to outline this data in the manuscript. What about palatability of cefadroxil given your angle on the data in the paediatric context? Are there any safety profile differences?
The results, discussion and conclusions are sound and the authors have appropriately mentioned the importance of more PK/PD data and clinical studies in their conclusion.

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Introduction
Line 62 Suggest referencing the sentence "However, three-times daily (TID) dosing is commonly used given concerns regarding adherence with QID dosing" could consider the recent publication https://journals.lww.com/pidj/Fulltext/2020/06000/Twice__and_Thrice_daily_Cephalexin_Dosin g_for.12.aspx Line 66 "cefadoxil is an appealing alternative to cephalexin based on its longer half-life, ~1.5-2 hours in adults (4, 5). While cephalexin is typically dosed 3-4 times per day, cefadroxil can likely be dosed 2-3 times per day (6)." Is this the dosing interval of 2-3 times per day recommended in adults or children or both, recommend specifying?
Line 59 "For oral therapy, cephalexin is most commonly used given its favorable side effect profile and low cost." Is there a reference for this at all and are you referring to in children (I think this is commonly the case in paediatrics but thought that in adults oxacillin is more commonly favoured but again jurisdiction dependent)?
For the below comments in the introduction and discussion respectively: Line 68 "Despite these theoretical benefits, cefadroxil has not gained widespread use, especially in pediatrics, in part due to the paucity of pediatric pharmacokinetic and pharmacodynamic (PK/PD) data and uncertainty about cefadroxil's range of minimum inhibitory concentrations line 144 "Given the limited data available, the concentrations needed for adequate time above our described MICs are likely achievable with commonly used oral dosing strategies" Is there any PK/PD data in children (even down to 12) for cefadroxil? If so it would be helpful for the reader to outline this data in the manuscript. What about palatability of cefadroxil given your angle on the data in the paediatric context? Are there any safety profile differences?
The results, discussion and conclusions are sound and the authors have appropriately mentioned the importance of more PK/PD data and clinical studies in their conclusion.

Response to Reviewers -Cefadroxil comparable to cephalexin: minimum inhibitory concentrations among methicillin-susceptible Staphylococcus aureus isolates from pediatric musculoskeletal infections
Corresponding Author: Andrew Haynes Reviewer #1 (Comments for the Author): Dr. Haynes and Colleagues present a brief report describing MICs to antistaphylococcal beta-lactams among pediatric MSSA musculoskeletal infection isolates. The overall object of this study is to evaluate the relative in vitro susceptibility of isolates to cefadroxil compared to other first generation cephalosporins (oxacillin and ceftaroline were also measured). While cephalexin is commonly used, use of cefadroxil may allow for fewer daily dose administrations. The paper does provide some information of clinical interest and the microbiologic methods appear sound. Appropriate controls were used. The paper would be improved by putting the results into context a bit more. It is difficult to appreciate the value of a given MIC without understanding what are the expected serum / tissue levels of drug.
My specific queries / comments / suggestions are listed below: 1. Introduction. The authors comment that some experts recommend thrice daily cephalexin rather than four times daily out of concerns for adherence. Of note, in two recent publications, MSSA osteoarticular infections were treated with three times daily cephalexin with high levels of treatment success (Ramchandar N, et al. 2020. Pediatr Infect Dis J 39:523-525;McNeil et al. Antimicrob Agents Chemother. 2020;64: e00703) and in one of these papers tid dosing was comparable to qid dosing in terms of efficacy (albeit uncontrolled and sample size limiting).
Response: Added references to these two papers as supporting clinical data.
2. Introduction. The authors write, "While cephalexin is typically dosed 3-4 times per day, cefadroxil can likely be dosed 2-3 times per day" and reference the package insert. Some expansion on this is probably warranted. Cefadroxil is approved for treatment of UTI, SSTI and streptococcal pharyngitis in children with daily or bid dosing. Why would three times daily dosing of cefadroxil be needed?
Response: The rationale for possibly needing TID dosing in osteomyelitis is to achieve higher T>MIC targets, and with higher probability of target attainment, given the seriousness of the infection, especially given the need for bone penetration. Cefadroxil is used for osteoarticular infections more commonly outside of the United States (where we are based). Cefadroxil is included in multiple treatment guidelines from Europe for osteomyelitis. In those guidelines, it is frequently dosed much higher than the FDA approved doses for UTI, SSTI, GAS pharyngitis, etc. Spanish guidelines (from Sociedad Espanola de Infectologia Pediatrica) recommend 90 mg/kg/day divided q8h, the French Pediatric Infectious Disease Group recommends 150 mg/kg/day in 3 divided doses, and the European Society for Pediatric Infectious Diseases (ESPID) recommends 75-150 mg/kg/day, in 3-4 doses. In line with these recommendations, a review paper on the treatment of pediatric osteomyelitis by DeRonde et al suggests 120mg/kg/day q8h. We have expanded the discussion of this in the manuscript to reflect this data and have included some of the above references.